Alcohol abuse/dependence (alcoholism) is a dangerous disorder, affecting a significant percentage of the population and killing many Americans each year. Identifying the underlying causes of this disorder is difficult because it is extremely complex, with multiple genetic and environmental influences. However, identification of specific gene(s) that influence risk for alcoholism and the mechanisms these genes work through will undoubtedly aid in prevention and treatment strategies for at-risk populations. Animal models are critical to the discovery of both genes and mechanisms underlying various components of this disorder because they share many human genes, but can be bred, raised and tested under controlled conditions, making it easier to identify genetic influences on ethanol behaviors associated with risk for developing alcoholism. In particular, the C57BL/6J and DBA/2J inbred mouse strains are ideal for alcohol addiction research because they differ dramatically in consumatory, withdrawal and conditioned responses to this drug. Using informative mapping populations derived from these two progenitor strains, we have identified a quantitative trait gene on chromosome 4 that influences ethanol withdrawal convulsion severity in mice. This gene, Mpdz, encodes for the MPDZ (multiple PDZ domain) protein, which interacts with a number of other proteins to increase intracellular signal fidelity. The mechanism(s) through which MPDZ works to influence ethanol withdrawal convulsions are currently unknown, as is Mpdz's influence on additional ethanol phenotypes. The purpose of this proposal is two-fold: first, we will expand our analysis of Mpdz's role in ethanol withdrawal to include other phenotypes (e.g., ethanol withdrawal anxiety, ethanol acceptance). Second, we will study potential mechanisms by which Mpdz can effect ethanol withdrawal severity by determining MPDZ's influence on GABA(B) and 5HT(2C) receptor function using the [35S]GTPyS binding assay and observing in vivo responses to changes in GABA(B) and 5HT(2C) receptor activation in a neural region associated with ethanol withdrawal. This proposal is relevant to public health because Mpdz is a gene also found in humans (MPDZ), and may influence alcohol withdrawal severity in a similar manner. Additionally, our identification of the mechanisms that Mpdz acts through to produce its ethanol withdrawal effects may aid in the identification of future therapeutic treatments for alcohol abuse. [unreadable] [unreadable] [unreadable]